Dynamic Changes in the NK-, Neutrophil-, and B-cell Immunophenotypes Relevant in High Metastatic Risk Post Neoadjuvant Chemotherapy-Resistant Early Breast Cancers

Gazinska, P; Milton, C; Iacovacci, J; Ward, J; Buus, R; Alaguthurai, T; Graham, R; Akarca, A; Lips, E; Naidoo, K; Wesseling, J; Marafioti, T; Cheang, M; Gillett, C; Wu, Y; Khan, A; Melcher, A; Salgado, R; Dowsett, M; Tutt, A; Roxanis, I; Haider, S; Irshad, S

Author(s): Gazinska, P; Milton, C; Iacovacci, J; Ward, J; Buus, R; Alaguthurai, T; Graham, R; Akarca, A; Lips, E; Naidoo, K; Wesseling, J; Marafioti, T; Cheang, M; Gillett, C; Wu, Y; Khan, A; Melcher, A; Salgado, R; Dowsett, M; Tutt, A; Roxanis, I; Haider, S; Irshad, S;
Details: Publication Year 2022-10-14,Volume 28,Issue #20,Page 4494-4508
Journal Title: Clinical Cancer Research
Publication Type: Research article
Abstract: PURPOSE: To identify potential immune targets in post-neoadjuvant chemotherapy (NAC)-resistant triple-negative breast cancer (TNBC) and ER+HER2- breast cancer disease. EXPERIMENTAL DESIGN: Following pathology review, 153 patients were identified as having residual cancer burden (RCB) II/III disease (TNBC n = 80; ER+HER2-n = 73). Baseline pre-NAC samples were available for evaluation for 32 of 80 TNBC and 36 of 73 ER+HER2- cases. Bright-field hematoxylin and eosin assessment allowed for tumor-infiltrating lymphocyte (TIL) evaluation in all cases. Multiplexed immunofluorescence was used to identify the abundance and distribution of immune cell subsets. Levels of checkpoints including PD-1/PD-L1 expression were also quantified. Findings were then validated using expression profiling of cancer and immune-related genes. Cytometry by time-of-flight characterized the dynamic changes in circulating immune cells with NAC. RESULTS: RCB II/III TNBC and ER+HER2- breast cancer were immunologically "cold" at baseline and end of NAC. Although the distribution of immune cell subsets across subtypes was similar, the mRNA expression profiles were both subtype- and chemotherapy-specific. TNBC RCB II/III disease was enriched with genes related to neutrophil degranulation, and displayed strong interplay across immune and cancer pathways. We observed similarities in the dynamic changes in B-cell biology following NAC irrespective of subtype. However, NAC induced changes in the local and circulating tumor immune microenvironment (TIME) that varied by subtype and response. Specifically, in TNBC residual disease, we observed downregulation of stimulatory (CD40/OX40L) and inhibitory (PD-L1/PD-1) receptor expression and an increase in NK cell populations (especially non-cytolytic, exhausted CD56dimCD16-) within both the local TIME and peripheral white cell populations. CONCLUSIONS: This study identifies several potential immunologic pathways in residual disease, which may be targeted to benefit high-risk patients.
Keywords: B7-H1 Antigen/genetics; *Breast Neoplasms/drug therapy/genetics/metabolism; Eosine Yellowish-(YS)/therapeutic use; Female; Hematoxylin; Humans; Neoadjuvant Therapy; Neutrophils/metabolism; Programmed Cell Death 1 Receptor/therapeutic use; RNA, Messenger; *Triple Negative Breast Neoplasms/drug therapy/genetics; Tumor Microenvironment
Department(s): Laboratory Research
PubMed ID: 36161312
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-22-0543
Open Access at Publisher's Site: https://doi.org/10.1158/1078-0432.Ccr-22-0543
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-25 06:46:51

Last Modified: 2024-10-25 06:48:14